Q&A: Unraveling the gut microbiome’s role in autoimmune biliary diseases
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Key takeaways:
- The liver’s production of bile acids is interwoven with the gut’s diverse microbial community.
- Despite treatment advances, the microbiome’s impact poses challenges in developing personalized therapies.
The relationship between the gut microbiome and autoimmune biliary diseases, such as primary biliary cholangitis and primary sclerosing cholangitis, has been the subject of considerable research.
In this exclusive Healio interview, Gideon Hirschfield, PhD, MB Bchir, the Lily and Terry Horner Chair in Autoimmune Liver Disease at the University of Toronto, discusses the latest insights into the gut microbiome’s role as a key player in disease development and progression.
Healio: How does the composition of the gut microbiome influence the development and progression of autoimmune biliary diseases?
Hirschfield: In all liver diseases, there is a tight association between the liver and the bowel. The liver makes bile acids, and the gut has many microbes and signaling pathways related to bile acid biology. In many liver diseases, including particularly autoimmune biliary diseases, if you measure the microbiome, you measure the totality, the species, the metabolism.
You see that there are differences at different times in patients, particularly with autoimmune biliary diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). What we are trying to understand is are those differences causal or consequential, and that is quite hard because as liver diseases progress, they impact the microbiome.
Studies have shown that changes in the microbiome, such as through fecal transplant, can improve conditions like encephalopathy. It is a fascinating area, not fully defined, but the diverse species in the bowel metabolize various molecules, including bile acids, influencing both colon mucosa immunologically and liver function indirectly. Factors such as diet, environment and medications also influence the microbiome, with implications for disease development in autoimmune biliary diseases like PBC and PSC.
Healio: How do environmental factors, including diet and lifestyle, affect the function of the gut microbiome in patients with autoimmune biliary diseases?
Hirschfield: We do not know enough, but there are significant geographic variations among populations, likely linked to different dietary patterns. High fish intake, high red meat consumption and the absence of animal protein might be deleterious. Observations from zoological studies suggest that dietary habits greatly influence the microbiome across species.
While I cannot provide definitive answers at the individual level, on a holistic level we have clues when considering diseases like PBC and PSC. For example, PBC is still more common in people who smoke, while PSC is typically a nonsmoker’s disease. PSC is often associated with inflammatory bowel disease, particularly colitis over Crohn’s disease.
There are also socioeconomic gradients of who develops PBC. I work in Ontario, Canada, which has a population around 15 million people: a very diverse area. Our data show a higher socioeconomic status among PSC patients. This infers a potential link between environment and microbiome, although it is important to recognize these as inferences rather than established data.
Healio: What challenges and/or limitations exist in studying the role of the microbiome in autoimmune biliary diseases?
Hirschfield: What we really need — and this takes resource and effort — is prospective studies. We need to follow patients over their journey of living with PBC and PSC, tracking their therapies such as ursodeoxycholic acid, bile acid sequestrants and emerging treatments. This entails serially monitoring patients and examining their stool, urine and blood as they progress through the disease over time.
It is hard because these are slowly progressive, rare diseases. We could probably learn more from highly detailed phenotyping studies in a small number of patients over a long duration than large, uncontrolled studies that lack the ability to observe changes over time.
Understanding the impact of new drugs is crucial. For example, we just published a phase 3 clinical trial in the New England Journal of Medicine on seladelpar. It is highly potent and improves itch. It would be interesting to investigate whether this therapeutic mechanism correlates with changes in the microbiome. Despite the difficulty of these studies, they offer invaluable insights into the workings of various molecules, such as [farnesoid X receptor (FXR)] agonists and [ileal bile acid transporter (IBAT)] inhibitors.
Healio: What recent research has looked at the efficacy of microbiome-targeted interventions in the management of biliary diseases?
Hirschfield: There has been a bit of research exploring different angles. There have been data around differences in microbiome and disease and risk. Specifically, in PSC, there has been interest in vancomycin because it is a hot topic, slightly controversial. There is a lot of interest in fecal transplantation, and there are a few studies and groups who are interested in determining whether fecal transplantation is a therapeutic option, particularly for a PBC. Additionally, researchers are beginning to investigate the concept of altering bile acid recirculation as a treatment for pruritus.
Healio: How could a better understanding of the microbiome lead to more personalized medicine approaches?
Hirschfield: We are all looking for treatments targeted to the biology. We have made a lot of progress in biliary disease and its treatments — ursodeoxycholic acid; FXR agonists, such as obeticholic acid; peroxisome proliferator-activated receptors, including seladelpar, elafibranor or bezafibrate; and fenofibrate. They are all targeting predominantly, we think, at the hepatocyte level. What we want is if there is a better cause, a better root cause.
Maybe the microbiome is coming proximal to what we are seeing in the liver. Maybe that explains why some patients are responders and other patients are not responders. We have the opportunity to then basically target therapy more around that individual patient’s journey, symptoms and response to current therapies. It is slightly aspirational.
But in a disease like PSC where there are no current therapies, we need to be creative and think about new ways of treating the disease. Maybe our efforts to always target the biliary epithelium are mistaken, and we should be targeting the colonic epithelium and the bowel bugs and viruses and fungi that live within the colon. Maybe we will then see a better impact and earlier impact, a more meaningful impact on the healing of the biliary tree.
It is really a route to try to overcome our roadblock, particularly in PSC, but also in PBC.
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